Influenza A virus (IAV) preferentially infects conducting airway and alveolar epithelial cells in the lung. The outcome of these infections is impacted by the host response, including the production of various cytokines, chemokines, and growth factors. Fibroblast growth factor-9 (FGF9) is required for lung development, can display antiviral activity in vitro , and is upregulated in asymptomatic patients during early IAV infection. We therefore hypothesized that FGF9 would protect the lungs from respiratory virus infection and evaluated IAV pathogenesis in mice that overexpress FGF9 in club cells in the conducting airway epithelium (FGF9-OE mice). However, we found that FGF9-OE mice were highly susceptible to IAV and Sendai virus infection compared to control mice. FGF9-OE mice displayed elevated and persistent viral loads, increased expression of cytokines and chemokines, and increased numbers of infiltrating immune cells as early as 1 day post-infection (dpi). Gene expression analysis showed an elevated type I interferon (IFN) signature in the conducting airway epithelium and analysis of IAV tropism uncovered a dramatic shift in infection from the conducting airway epithelium to the alveolar epithelium in FGF9-OE lungs. These results demonstrate that FGF9 signaling primes the conducting airway epithelium to rapidly induce a localized IFN and proinflammatory cytokine response during viral infection. Although this response protects the airway epithelial cells from IAV infection, it allows for early and enhanced infection of the alveolar epithelium, ultimately leading to increased morbidity and mortality. Our study illuminates a novel role for FGF9 in regulating respiratory virus infection and pathogenesis.
Abstract Background The formation of supernumerary teeth is an excellent model for studying the molecular mechanisms that control stem/progenitor cell homeostasis needed to generate a renewable source of replacement cells and tissues. Although multiple growth factors and transcriptional factors have been associated with supernumerary tooth formation, the regulatory inputs of extracellular matrix in this regenerative process remains poorly understood. Results In this study, we present evidence that disrupting glycosaminoglycans (GAGs) in the dental epithelium of mice by inactivating FAM20B, a xylose kinase essential for GAG assembly, leads to supernumerary tooth formation in a pattern reminiscent of replacement teeth. The dental epithelial GAGs confine murine tooth number by restricting the homeostasis of Sox2(+) dental epithelial stem/progenitor cells in a non-autonomous manner. FAM20B-catalyzed GAGs regulate the cell fate of dental lamina by restricting FGFR2b signaling at the initial stage of tooth development to maintain a subtle balance between the renewal and differentiation of Sox2(+) cells. At the later cap stage, WNT signaling functions as a relay cue to facilitate the supernumerary tooth formation. Conclusions The novel mechanism we have characterized through which GAGs control the tooth number in mice may also be more broadly relevant for potentiating signaling interactions in other tissues during development and tissue homeostasis.
Lung mesenchyme is a critical determinant of the shape and size of the lung, the extent and patterning of epithelial branching, the formation of the pulmonary vasculature, and the formation of mesenchymal components of the adult lung. Fibroblast Growth Factor 9 (FGF9) is expressed in developing lung epithelium and mesothelium and has an essential primary role in regulating mesenchymal growth and differentiation through signaling to mesenchymal FGF receptors (FGFRs) 1 and 2. Pleuropulmonary Blastoma (PPB) is a pediatric lung cancer syndrome with onset in late gestation and early childhood. PPB is a unique lung cancer in that its cellular origins are derived from lung mesenchyme. Germline loss‐of‐function mutations in Dicer1 , an essential gene for the production of microRNAs, predisposes to PPB in humans. In this talk I will discus mechanisms by which FGF9 regulates mesenchymal growth and differentiation, evidence that Fgf9 may be regulated by microRNAs during lung development, and evidence that FGF9 may be an important factor for the initiation PPB. This work is funded by a grant from the March of Dimes foundation.
Errors in clinical decision-making are disturbingly common. Here, we show that structured information–sharing networks among clinicians significantly reduce diagnostic errors, and improve treatment recommendations, as compared to groups of ...Errors in clinical decision-making are disturbingly common. Recent studies have found that 10 to 15% of all clinical decisions regarding diagnoses and treatment are inaccurate. Here, we experimentally study the ability of structured information–sharing ...
